Adaptation in protein fitness landscapes is facilitated by indirect paths

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Abstract

The structure of fitness landscapes is critical for understanding adaptive protein evolution. Previous empirical studies on fitness landscapes were confined to either the neighborhood around the wild type sequence, involving mostly single and double mutants, or a combinatorially complete subgraph involving only two amino acids at each site. In reality, the dimensionality of protein sequence space is higher (20^L) and there may be higher-order interactions among more than two sites. Here we experimentally characterized the fitness landscape of four sites in protein GB1, containing 20⁴ = 160,000 variants. We found that while reciprocal sign epistasis blocked many direct paths of adaptation, such evolutionary traps could be circumvented by indirect paths through genotype space involving gain and subsequent loss of mutations. These indirect paths alleviate the constraint on adaptive protein evolution, suggesting that the heretofore neglected dimensions of sequence space may change our views on how proteins evolve.

Data availability

The following data sets were generated

1. NC Wu
2. L Dai
3. CA Olson
4. JO Lloyd-Smith
5. R Sun
(2015) Streptococcus dysgalactiae strain:GB1_AO
Publicly available at the NCBI Gene Expression Omnibus (Accession no: PRJNA278685).

https://www.ncbi.nlm.nih.gov/bioproject/PRJNA278685/

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Author details

Nicholas Wu

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.
Lei Dai

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Clifford Anders Olson

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
James O Lloyd-Smith

Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7941-502X
Ren Sun

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States

For correspondence
rsun@mednet.ucla.edu

Competing interests
The authors declare that no competing interests exist.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.